ROR gamma (RORγ) modulators

ABSTRACT

The compounds can be used as inhibitors of RORγ and are useful for the treatment of RORγ mediated diseases.

This application claims priority benefit of European patent application16202175.2, filed Dec. 5, 2016, the disclosure of which is incorporatedherein by reference in its entirety.

The present application relates to compounds that are modulators ofRORγ, to pharmaceutical compositions comprising the same and to theiruse for the treatment of RORγ-mediated diseases or conditions, inparticular autoimmune diseases and inflammatory diseases.

T helper (T_(H)) cells play a crucial role in the adaptive immune systemas they coordinate defense against specific pathogens. The interleukin17 (IL-17) producing lineages of T_(H) cells, such as T_(H)17 cells,have been directly implicated in the pathology of a multitude ofautoimmune and inflammatory diseases, including, but not limited to,psoriasis, multiple sclerosis, rheumatoid arthritis, Crohn's disease,asthma, chronic obstructive pulmonary disease, atopic dermatitis,psoriatic arthritis, ankylosing spondylitis and irritable bowel disease.

Interleukin 17 and interleukin 23 (IL-23) are two pivotal cytokines inT_(H)17 biology. IL-17 is secreted by T_(H)17 cells and is a potentinducer of tissue inflammation; IL-23 has been shown to be a keyparticipant in amplifying and stabilizing the proliferation of theT_(H)17 cell type via the IL-23 receptor (IL-23R).

The retinoic-acid-receptor-related orphan receptor γt (RORγt) acts as amaster regulator of the development of T_(H)17 cells, and also as acritical component in non-T_(H)17 IL-17 producing cells, such as forexample γδ T-cells. The ROR gene family is part of the nuclear hormonereceptor superfamily, and consists of three members (RORα, RORβ, andRORγ). Each gene is expressed in different isoforms, differing foremostin their N-terminal sequence. Two isoforms of RORγ have been identified:RORγ1 and RORγ2 (also known as RORγt). The term RORγ is used here todescribe both RORγ1 and/or RORγ2.

RORγ modulator compounds have been described in the international patentapplication WO2015/082533.

Given the important role of RORγ in immune and inflammatory disorders,it is desirable to prepare modulators of RORγ with improved safetyprofiles which can be used in the treatment of RORγ mediated diseases.The present application provides such novel RORγ modulator compoundswith improved safety profiles.

The present application thus provides novel RORγ modulator compoundsrepresented by the (Formula I):

and the absolute configuration of compound (I) corresponds to compoundsof (Formula IA) or (Formula IB):

2-{4-[(cyclopropylmethyl)sulfonyl]phenyl}-N-{4-[(1R)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}acetamideor a pharmaceutically acceptable salt thereof.

2-{4-[(cyclopropylmethyl)sulfonyl]phenyl}-N-{4-[(1S)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}acetamideor a pharmaceutically acceptable salt thereof.

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the elements of this present application herein.

The term pharmaceutically acceptable salt of the compound represented bythe aforementioned (Formula I), (Formula IA) or (Formula IB) representsthose salts which are, within the scope of medical judgment, suitablefor use in contact with the tissues of humans and lower animals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. The acid function of thecompound can be reacted with an organic or a mineral base, like sodiumhydroxide, potassium hydroxide or lithium hydroxide.

In addition to the compound represented by the aforementioned (FormulaI), (Formula IA) or (Formula IB), a pharmaceutically acceptable saltthereof, their solvates and hydrates also fall within the scope of thepresent application.

In another aspect of the present application, it was discovered that thecompound of the present application (Formula I), (Formula IA) or(Formula IB) could also be administered as prodrug.

The prodrugs are defined as compounds of (Formula VI), (Formula VIA),(Formula VIB), (Formula VIC) or (Formula VID) where they correspond tocompounds of (Formula I), (Formula IA) or (Formula IB) with a sulfinylgroup instead of a sulfonyl group. Absolute configuration of chiralcenters of prodrugs were not determined and were arbitrarily assigned.It is known by the man skilled in the art that sulfoxides might displayimproved aqueous solubility when compared to their sulfone counterparts.

2-[4-(cyclopropylmethylsulfinyl)phenyl]-N-[4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide.

(−)-2-[4-[(S)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1R)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamideor a pharmaceutically acceptable salt thereof.

(−)-2-[4-[(S)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1S)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamideor a pharmaceutically acceptable salt thereof.

(+)-2-[4-[(R)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1R)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamideor a pharmaceutically acceptable salt thereof.

(+)-2-[4-[(R)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1S)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamideor a pharmaceutically acceptable salt thereof.

Further, the compounds of the present application present no significanttoxicities and thus are suitable to be used in a medicament.

The compounds of the application inhibit RORγ activity. Modulation ofRORγ activity can be measured using for example biophysical (natural)ligand displacement studies, biochemical AlphaScreen or FRET assays,cellular GAL4 reporter gene assays, cellular IL-17 promoter reporterassay or functional IL-17 ELISA assays using for example mousesplenocytes or human peripheral blood mononuclear cells (PBMCs) culturedunder T_(H)17 polarizing conditions.

In such assays, the interaction of a compound with RORγ can bedetermined by measuring, for example, the compound modulated interactionof cofactor-derived peptides with the RORγ ligand binding domain (IC₅₀),or measuring the gene products of compound modulated RORγ mediatedtranscription using, for example, luciferase reporter assays or IL-17ELISA assays.

The skilled artisan will recognize that desirable IC₅₀ values aredependent on the compound tested. For example, a compound with an IC₅₀value against the biological target less than 10⁻⁵ M is generallyconsidered as a candidate for drug selection. In some embodiments, thisvalue is lower than 10⁻⁶ M.

The safety profile was assessed by human ether-à-go-go-related gene(hERG) ion channel inhibition and CYP3A4 inhibition.

The human ether-à-go-go-related gene (hERG, Kv 11.1) channel plays anespecially important role in cardiac safety, and the hERG patch clampassay is a key regulatory requirement before first-in-man clinicaltrials (FDA guidance).

Inhibition of the hERG current (IKr), involved in the repolarisationphase of the cardiac action potential, has been shown to prolong thecardiac action potential and to cause QT interval prolongation inelectrocardiogram resulting in an increase of the risk for potentiallyfatal ventricular arrhythmias called “Torsade de Pointes” in humans.

The hERG assay, in which hERG is brought to expression in CHO cells,provides information of the interaction of a compound with the hERGchannel. The amplitude of hERG potassium channel tail currents arerecorded under control and the compound solution at differentconcentrations. Then the IC₅₀ value is determined from the dose-responsecurve.

The identification of CYP3A4 inhibition as early as possible in drugdiscovery is key to prevent potential adverse toxic effects related todrug-drug interactions (FDA guidance).

In the CYP3A4 inhibition assay, in vitro IC₅₀ of a test compound asdirect inhibitor against CYP3A4 is determined, by measuring theinhibition of the turn-over of probe substrates of CYP3A4 (Midazolam andTestosterone) to their specific metabolites i.e., 1′-Hydroxymidazolam,6ß-Hydroxytestosterone, in human liver microsomes.

The skilled artisan will recognize that desirable IC₅₀ values aredependent on the compound tested. For example, the higher the IC₅₀values are in above tests, the better the safety profile will be, withdecreased risks of cardiac safety issues and potential adverse toxiceffects related to drug-drug interactions.

The present application also relates to a pharmaceutical compositioncomprising a compound of (Formula I), (Formula IA) or (Formula IB) orpharmaceutically acceptable salt thereof of compounds in admixture withpharmaceutically acceptable excipients and optionally othertherapeutically active agents.

The present application also relates to a pharmaceutical compositioncomprising a compound of (Formula IA) or (Formula IB) orpharmaceutically acceptable salt thereof of compounds in admixture withpharmaceutically acceptable excipients and optionally othertherapeutically active agents.

The present application also relates to a pharmaceutical compositioncomprising a compound of (Formula I), (Formula IA) or (Formula IB) orpharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.

The present application also relates to a pharmaceutical compositioncomprising a compound of (Formula IA) or (Formula IB) or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.

The excipients must be “acceptable” in the sense of being compatiblewith the other ingredients of the composition and not deleterious to therecipients thereof.

The present application also relates to a pharmaceutical compositioncomprising at least one additional therapeutically active agent.

The application further includes a compound of (Formula I), (Formula IA)or (Formula IB) in combination with one or more other drug(s).

The application further includes a compound of (Formula IA) or (FormulaIB) in combination with one or more other drug(s).

Compositions include, e.g., those suitable for oral, sublingual,subcutaneous, intravenous, intramuscular, nasal, local, or rectaladministration, and the like, all in unit dosage forms foradministration.

For oral administration, the compound of the application may bepresented as discrete units, such as tablets, capsules, powders,granulates, solutions, suspensions, and the like.

For parenteral administration, the pharmaceutical composition of thecompound of the application may be presented in unit-dose or multi-dosecontainers, e.g. injection liquids in predetermined amounts, for examplein sealed vials and ampoules, and may also be stored in a freeze dried(lyophilized) condition requiring only the addition of sterile liquidcarrier, e.g. water, prior to use.

Mixed with such pharmaceutically acceptable excipients, the active agentmay be compressed into solid dosage units, such as pills, tablets, or beprocessed into capsules or suppositories. By means of pharmaceuticallyacceptable liquids, the active agent can be applied as a fluidcomposition, e.g. as an injection preparation, in the form of asolution, suspension, emulsion, or as a spray, e.g. a nasal spray.

For making solid dosage units, the use of conventional additives such asfillers, colorants, polymeric binders and the like is contemplated. Ingeneral any pharmaceutically acceptable excipients, which do notinterfere with the function of the active compounds can be used.Suitable excipients with which the compound of the application can beadministered as solid compositions include lactose, starch, cellulosederivatives and the like, or mixtures thereof, used in suitable amounts.For parenteral administration aqueous suspensions, isotonic salinesolutions and sterile injectable solutions may be used, containingpharmaceutically acceptable dispersing agents and/or wetting agents,such as propylene glycol or butylene glycol.

The application further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable forsaid composition, said packaging material including instructions for theuse of the composition for the use as hereinbefore described.

The exact dose and regimen of administration of the compound of theapplication, or a pharmaceutical composition thereof, may vary with theparticular compound, the route of administration, and the age andcondition of the individual subject to whom the medicament is to beadministered.

In general parenteral administration requires lower dosages than othermethods of administration, which are more dependent upon absorption.However, a dosage for humans preferably contains 0.0001-100 mg per kgbody weight. The desired dose may be presented as one dose or asmultiple sub-doses administered at appropriate intervals throughout theday.

The compounds of (Formula I), (Formula IA) or (Formula IB) according tothe application or a pharmaceutically acceptable salt thereof can beused as medicament.

The compounds of (Formula IA) or (Formula IB) according to theapplication or a pharmaceutically acceptable salt thereof can be used asmedicament.

The compounds of (Formula I), (Formula IA) or (Formula IB) according tothe application or a pharmaceutically acceptable salt thereof can beused as medicament in therapy.

The compounds of (Formula IA) or (Formula IB) according to theapplication or a pharmaceutically acceptable salt thereof can be used asmedicament in therapy.

A further aspect of the application resides in the use of compounds of(Formula I), (Formula IA) or (Formula IB) according to the applicationor a pharmaceutically acceptable salt thereof in therapy.

A further aspect of the application resides in the use of compounds of(Formula IA) or (Formula IB) according to the application or apharmaceutically acceptable salt thereof in therapy.

A further aspect of the application resides in the use of compounds of(Formula I), (Formula IA) or (Formula IB) according to the applicationor a pharmaceutically acceptable salt thereof for the treatment ofRORγ-mediated diseases or RORγ mediated conditions.

A further aspect of the application resides in the use of compounds of(Formula IA) or (Formula IB) according to the application or apharmaceutically acceptable salt thereof for the treatment ofRORγ-mediated diseases or RORγ mediated conditions.

Another aspect of the application resides in the use of compounds of(Formula I), (Formula IA) or (Formula IB) according to the applicationor a pharmaceutically acceptable salt thereof for the treatment ofautoimmune diseases, in particular those diseases in which T_(H)17 cellsand non-T_(H)17 cells, which express T_(H)17 hallmark cytokines, play aprominent role.

Another aspect of the application resides in the use of compounds of(Formula IA) or (Formula IB) according to the application or apharmaceutically acceptable salt thereof for the treatment of autoimmunediseases, in particular those diseases in which T_(H)17 cells andnon-T_(H)17 cells, which express T_(H)17 hallmark cytokines, play aprominent role.

These include, but are not limited to, the treatment of rheumatoidarthritis, psoriasis, inflammatory bowel disease, Crohn's disease andmultiple sclerosis.

In another aspect, compounds of (Formula I), (Formula IA) or (FormulaIB) according to the application or a pharmaceutically acceptable saltthereof can be used for treatment of inflammatory diseases in whichT_(H)17 cells and/or non-T_(H)17 cells, which express T_(H)17 hallmarkcytokines, play a prominent role such as, but not limited to respiratorydiseases, osteoarthritis and asthma.

In another aspect, compounds of (Formula IA) or (Formula IB) accordingto the application or a pharmaceutically acceptable salt thereof can beused for treatment of inflammatory diseases in which T_(H)17 cellsand/or non-T_(H)17 cells, which express T_(H)17 hallmark cytokines, playa prominent role such as, but not limited to respiratory diseases,osteoarthritis and asthma.

Also, compounds of (Formula I), (Formula IA) or (Formula IB) or apharmaceutically acceptable salt thereof can be used for treatment ofinfectious diseases in which T_(H)17 cells and/or non-T_(H)17 cells,which express T_(H)17 hallmark cytokines, play a prominent role such as,but not limited to mucosal leishmaniasis.

Also, compounds of (Formula IA) or (Formula IB) or a pharmaceuticallyacceptable salt thereof can be used for treatment of infectious diseasesin which T_(H)17 cells and/or non-T_(H)17 cells, which express T_(H)17hallmark cytokines, play a prominent role such as, but not limited tomucosal leishmaniasis.

Compounds of (Formula I), (Formula IA) or (Formula IB) according to theapplication or a pharmaceutically acceptable salt thereof can also beused for treatment of other diseases in which T_(H)17 cells and/ornon-T_(H)17 cells, which express T_(H)17 hallmark cytokines, play aprominent role such as, but not limited to Kawaski disease andHashimoto's thyroiditis.

Compounds of (Formula IA) or (Formula IB) according to the applicationor a pharmaceutically acceptable salt thereof can also be used fortreatment of other diseases in which T_(H)17 cells and/or non-T_(H)17cells, which express T_(H)17 hallmark cytokines, play a prominent rolesuch as, but not limited to Kawaski disease and Hashimoto's thyroiditis.

In yet another aspect, the application resides in the use of compoundsof (Formula I), (Formula IA) or (Formula IB) according to theapplication or a pharmaceutically acceptable salt thereof for thetreatment of multiple sclerosis, inflammatory bowel disease, Crohn'sdisease, psoriasis, rheumatoid arthritis, asthma, osteoarthritis,Kawaski disease, Hashimoto's thyroiditis, cancer and mucosalleishmaniasis.

In yet another aspect, the application resides in the use of compoundsof (Formula IA) or (Formula IB) according to the application or apharmaceutically acceptable salt thereof for the treatment of multiplesclerosis, inflammatory bowel disease, Crohn's disease, psoriasis,rheumatoid arthritis, asthma, osteoarthritis, Kawaski disease,Hashimoto's thyroiditis, cancer and mucosal leishmaniasis.

In another aspect, the compounds of (Formula I), (Formula IA) or(Formula IB) according to the application or a pharmaceuticallyacceptable salt thereof for the preparation of a medicament can be usedin therapies to treat or prevent multiple sclerosis, inflammatory boweldisease, Crohn's disease, psoriasis and rheumatoid arthritis, asthma,osteoarthritis, Kawaski disease, Hashimoto's thyroiditis, cancer andmucosal leishmaniasis.

In another aspect, the compounds of (Formula IA) or (Formula IB)according to the application or a pharmaceutically acceptable saltthereof for the preparation of a medicament can be used in therapies totreat or prevent multiple sclerosis, inflammatory bowel disease, Crohn'sdisease, psoriasis and rheumatoid arthritis, asthma, osteoarthritis,Kawaski disease, Hashimoto's thyroiditis, cancer and mucosalleishmaniasis.

In another aspect, the compounds of (Formula I), (Formula IA) or(Formula IB) according to the application or a pharmaceuticallyacceptable salt thereof can be used to treat or prevent psoriasis.

In another aspect, the compounds of (Formula IA) or (Formula IB)according to the application or a pharmaceutically acceptable saltthereof can be used to treat or prevent psoriasis.

In yet another aspect, the compounds of (Formula I), (Formula IA) or(Formula IB) according to the application or a pharmaceuticallyacceptable salt thereof can be used to treat inflammatory bowel disease.

In yet another aspect, the compounds of (Formula IA) or (Formula IB)according to the application or a pharmaceutically acceptable saltthereof can be used to treat inflammatory bowel disease.

Herein is also provided a method of treating multiple sclerosis,inflammatory bowel disease, Crohn's disease, psoriasis and rheumatoidarthritis, asthma, osteoarthritis, Kawaski disease, Hashimoto'sthyroiditis, cancer and mucosal leishmaniasis comprising administeringto a patient in need thereof a therapeutically effective amount of(Formula I), (Formula IA) or (Formula IB) or a pharmaceuticallyacceptable salt thereof.

Herein is also provided a method of treating multiple sclerosis,inflammatory bowel disease, Crohn's disease, psoriasis and rheumatoidarthritis, asthma, osteoarthritis, Kawaski disease, Hashimoto'sthyroiditis, cancer and mucosal leishmaniasis comprising administeringto a patient in need thereof a therapeutically effective amount ofcompounds of (Formula VI), (Formula VIA), (Formula VIB), (Formula VIC)or (Formula VID) or a pharmaceutically acceptable salt thereof.

The phrase “therapeutically effective amount,” as used herein, means theamount of the subject compound or composition that is effective inproducing the desired therapeutic effect.

EXAMPLES

The present application will be explained with reference to examples.However, the scope of the present application is not limited to thefollowing examples.

The compounds of the application can be readily prepared according tothe following reaction scheme, or modifications thereof, using readilyavailable starting materials, reagents or previously describedintermediates and conventional synthesis procedures.

The abbreviations used in this scheme and these experimental details arelisted below and additional ones should be considered known to a personskilled in the art of synthetic chemistry.

Abbreviations used herein are as follow: TMSCF₃:Trifluoromethyltrimethylsilane; TBAF: Tetra-N-butylammonium fluoride;TMS: Trimethylsilyl; LiHMDS: Lithium bis(trimethylsilyl)amide;Pd₂(dba)₃: Tris(dibenzylideneacetone)dipalladium(0); T3P:1-Propanephosphonic anhydride; DIPEA: Diisopropylethylamine,N-ethyl-N-isopropyl-propan-2-amine; RT: room temperature; DMF:Dimethylformamide; CH₂Cl₂, DCM: dichloromethane; THF: Tetrahydrofuran;Et₂O: Diethyl ether; DMSO: Dimethylsulfoxide; EtOH: Ethanol; TLC: ThinLayer Chromatography; EtOAc: ethyl acetate; ACN, CH₃CN: acetonitrile;MeOH: methanol; TFA: Trifluoroacetic acid; HCl: Hydrochloric acid; Et₃N,TEA: triethylamine; NaCl: sodium chloride; NaHCO₃: sodium bicarbonate;H₂O: water; MgSO₄: magnesium sulfate; Na₂SO₄: sodium sulfate.

Chemical names are preferred IUPAC names, generated using Accelrys Draw4.1.

If a chemical compound is referred to using both a chemical structureand a chemical name, and an ambiguity exists between the structure andthe name, the structure predominates.

Example 12-[4-(cyclopropylmethylsulfonyl)phenyl]-N-[4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide

Step 1

To a solution of 1-(4-bromophenyl)-2,2-difluoro-ethanone (10.5 g) in 100mL THF at 0° C. under argon was added TMSCF₃ (12.7 g) followed byaddition of a 1 M solution of TBAF in THF (90 mL) over 45 minutes. Thereaction mixture was stirred for 1 hour at RT, then diluted with Et₂O(200 mL), washed with water (2×200 mL), brine (100 mL), dried andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel, using 0% to 20% EtOAc in cyclohexane asthe eluent to give 11.5 g (84%) of2-(4-bromophenyl)-1,1,1,3,3-pentafluoro-propan-2-ol as a yellow oil.

MS(ES⁺) m/z 302.9/304.9 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ ppm 6.70 (t, J=53.1 Hz, 2H), 7.60 (d, J=9.2Hz, 2H), 7.69 (d, J=9.2 Hz, 2H), 7.92 (s, 1H).

Step 2

To a solution of 2-(4-bromophenyl)-1,1,1,3,3-pentafluoro-propan-2-ol(11.4 g) in THF (100 mL) under argon was added a 1 M solution of LiHMDSin THF (112 mL), 2-(dicyclohexylphosphino)biphenyl (1.6 g) followed byaddition of Pd₂(dba)₃ (2.16 g). The reaction mixture was stirred underreflux for 1 hour, then cooled to 0° C., and a 12N aqueous solution ofHCl (15 mL) was added dropwise. After stirring for 1 hour at RT, thereaction mixture was poured onto a saturated aqueous solution of NaHCO₃(400 mL) then extracted with EtOAc (2×300 mL). The combined organiclayers were dried and concentrated under reduced pressure. The productwas precipitated in DCM, filtered and washed with a minimal amount ofDCM to give the desired product (4.75 g). The filtrate was purified bycolumn chromatography on silica gel, using 0% to 50% EtOAc incyclohexane as the eluent to give 1.4 g of the desired product.2-(4-Aminophenyl)-1,1,1,3,3-pentafluoro-propan-2-ol (6.15 g, 68%) wasobtained as an off-white solid.

MS(ES⁺) m/z 242.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ ppm 5.27 (s, 2H), 6.22-6.74 (m, 3H),7.11-7.35 (m, 3H).

Step 3

To a solution of 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol(0.55 g) in DCM (10 mL) were added2-[4-(cyclopropylmethylsulfonyl)phenyl]acetic acid (0.58 g) andN-ethyl-N-isopropyl-propan-2-amine (1.19 mL) followed by dropwiseaddition of a 50% solution of T3P in DCM (0.8 mL). The reaction mixturewas stirred at RT for 2 hours. EtOAc (100 mL) and water (100 mL) wereadded. The organic layer was separated, washed with brine (100 mL),dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was triturated in DCM (5 mL), filtered and washed with 10% DCMin pentane (5 mL) then dried to give 0.72 g (66%) of2-[4-(cyclopropylmethylsulfonyl)phenyl]-N-[4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamideas an off-white solid.

MS(ES⁺) m/z 478.1 [M+H]⁺.

Examples 2 and 3

The two enantiomers were separated from Example 1 by chiralchromatography using a column Chiralpak AD 20 μm, 76.5×350 mm and amobile phase, EtOH:MeOH 90:10, 350 mL/min, with UV detection at 254 nm.

Starting from 5 g of racemate in 500 mL of EtOH, five injections of thesolution were done to yield, after concentration, 2.17 g of Example 2(first enantiomer to be eluted) and 2.02 g of Example 3.

Example 2—Compound of (Formula IA):(+)-2-[4-(cyclopropylmethylsulfonyl)phenyl]-N-[4-[(1R)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide

MS(ES⁺) m/z 478.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ ppm 0.11 (m, 2H), 0.44 (m, 2H), 0.82 (m,1H), 3.24 (d, J=7.2 Hz, 2H), 3.82 (s, 3H), 6.67 (t, J=53.4 Hz, 2H), 7.57(d, J=9.2 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.67 (d, J=9.2 Hz, 2H), 7.70(s, 1H), 7.86 (d, J=8.5 Hz, 2H), 10.42 (s, 1H).

Optical rotation: [α]_(D) ²⁰=+1.5° (c=3 mg/mL, DMSO).

Example 3—Compound of (Formula IB):(−)-2-[4-(cyclopropylmethylsulfonyl)phenyl]-N-[4-[(1S)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide

MS(ES⁺) m/z 478.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ ppm 0.11 (m, 2H), 0.44 (m, 2H), 0.82 (m,1H), 3.24 (d, J=7.2 Hz, 2H), 3.82 (s, 3H), 6.67 (t, J=53.4 Hz, 2H), 7.56(d, J=9.2 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 7.67 (d, J=9.2 Hz, 2H), 7.70(s, 1H), 7.86 (d, J=8.5 Hz, 2H), 10.42 (s, 1H).

Optical rotation: [α]_(D) ²⁰=−4.6° (c=3 mg/mL, DMSO).

Example 4—X-Ray Single Crystal Diffraction

The absolute configuration of Examples 2 and 3 has been determined fromX-ray Single Crystal Diffraction (XRSCD) data using anomalous dispersionand Bijvoet differences analysis.

A single crystal of suitable crystallographic quality for crystalstructure determination from single crystal diffraction data has beenisolated from a slow evaporation experiment of a solution of Examples 2and 3 in chloroform.

Absolute Configuration of Example 2

Data have been collected on a Bruker Smart Apex single crystaldiffractometer. A molybdenum IμS microfocus X-ray source has been used,running at 50 kV and 0.6 mA, emitting Mo—Kα radiation (λ=0.710731 Å). ACharge-Coupled Device (CCD chip: 4K, 62 mm) area detector has beenpositioned at 6.0 cm. An Oxford Cryosystems nitrogen cryostat(Cryostream Plus 700 series) has allowed XRSCD experiment to be carriedout at 100 K. The single crystal with a size of: 25×250×250 μm³ has beenmounted from a Paratone N™ oil drop onto a low background mylar MiTeGenloop. A full Ewald sphere of reflections has been collected (3 omegascans of 680 frames with a frame width of 0.3°). Accumulation time hasbeen set at 80 seconds for each frame to be acquired.

The orientation matrix and unit cell have been established usingCELL_NOW (v2008/4) program. The 3D reflection profile and theintegration of all reflections have been carried out with the SAINT(v8.34A) program. The TWINABS (v2012/1) program has been used to correctfor Lorentz and polarization effects and for absorption by the sample.In addition, both HKLF4 and HKLF5 data has been generated respectivelyfor solving and refining by the SHELXTL (v2014/7) program suite.

The crystal structure data are as follows:

-   -   Triclinic, space group P1    -   a=7.9892(13) Å, b=11.4301(18) Å, c=11.6936(19) Å    -   α=83.022(2)°, β=77.006(2)°, γ=81.071(2)°    -   V=1023.7(3) Å³, Z=2, T=100(2) K,    -   11704 reflections measured (3.6≤2θ≤58.2), 11704 unique        (R_(sigma)=0.0229)    -   736 parameters and 3 restraints

The final R₁ is 2.7% (I>2σ(I)) and wR₂ is 7.1% (all data) withGof=1.030.

The standard procedure for the determination of the absolute structurewith X-ray diffraction techniques is based on the determination of theFlack parameter (x) with its associated standard uncertainty as part ofthe least-squares refinement procedure. Expected values are 0 (within 3esd's) for correct and +1 for inverted absolute structure. In case ofExample 2—compound of (Formula IA), Flack x=0.095(33) by classical fitto all intensities and 0.072(21) from 3969 selected quotients (Parsons'method giving a higher precision) indicate that Example 2—compound of(Formula IA) absolute configuration has been reliably determined.

In addition a post-refinement procedure based on a Bayesian statisticsapproach was applied (a completely different way from Flack approach).Using a combination of maximum likelihood estimation and Bayesianstatistics it not only gets a qualitative assignment of the absolutestructure, but also a quantitative estimate of the reliability of thatassignment. Analysis of Example 2—compound of (Formula IA) absolutestructure using likelihood method has been performed using Olex2software package. The resulting value is Hooft y=0.13(5) indicating thatthe absolute structure has been determined correctly (Bijvœt pairanalysis using Student's t distribution with 88% Bijvœt pairs coverage:4639 pairs used). The method has also calculated that the probabilitythat the structure is inverted is equal to zero.

Thus, these results indicate that the absolute configuration of Example2—compound of (Formula IA) is R (probability of 100%).

Absolute Configuration of Example 3

Data have been collected on a Bruker Smart Apex single crystaldiffractometer. A molybdenum IμS microfocus X-ray source has been used,running at 50 kV and 0.6 mA, emitting Mo—Kα radiation (λ=0.710731 Å). ACharge-Coupled Device (CCD chip: 4K, 62 mm) area detector has beenpositioned at 6.0 cm. An Oxford Cryosystems nitrogen cryostat(Cryostream Plus 700 series) has allowed XRSCD experiment to be carriedout at 100 K. The single crystal with a size of: 40×150×200 μm³ has beenmounted from a Paratone N™ oil drop onto a low background mylar MiTeGenloop. A full Ewald sphere of reflections has been collected (3 omegascans of 680 frames with a frame width of 0.3°). Accumulation time hasbeen set at 75 seconds for each frame to be acquired.

The orientation matrix and unit cell has been established using theBruker AXS Apex2 (v2014.11 0) program suite. The 3D reflection profileand the integration of all reflections have been carried out with theSAINT (v8.34A) program. The SADABS (v2014/5) program has been used tocorrect for Lorentz and polarization effects and for absorption by thesample. The tentative space group has been determined with the XPREP(v2014/2) program. The SHELXTL XT (v2014/4) program has been used tosolve the structure by the intrinsic phasing method. The SHELXTL XLMP(v2014/7) program has been used to refine the solution by full-matrixleast-squares calculations on F².

The crystal structure data are as follows:

-   -   Triclinic, space group P1    -   a=8.0022(5) Å, b=11.4394(8) Å, c=11.7044(8) Å    -   α=83.0030(10)°, β=76.9840(10)°, γ=80.9850(10)°    -   V=1026.83(12) A³, Z=2, T=100(2) K    -   10430 reflections measured (3.6≤2θ≤57.8), 8932 unique        (R_(int)=0.0081)    -   737 parameters and 3 restraints

The final R₁ was 2.5% (I>2σ(I)) and wR₂ was 6.8% (all data) withGof=1.024.

The standard procedure for the determination of the absolute structurewith X-ray diffraction techniques is based on the determination of theFlack parameter (x) with its associated standard uncertainty as part ofthe least-squares refinement procedure. Expected values are 0 (within 3esd's) for correct and +1 for inverted absolute structure. In case ofExample 3—compound of (Formula IB), Flack x=0.063(47) by classical fitto all intensities and 0.058(9) from 3969 selected quotients (Parsons'method giving a higher precision) indicate that Example 3—compound of(Formula IB) absolute configuration has been reliably determined. Inaddition a post-refinement procedure based on a Bayesian statisticsapproach was applied. Using a combination of maximum likelihoodestimation and Bayesian statistics it not only gets a qualitativeassignment of the absolute structure, but also a quantitative estimateof the reliability of that assignment.

Analysis of Example 3—compound of (Formula IB) absolute structure usinglikelihood method has been performed using Olex2 software package. Theresulting value is Hooft y=0.059(8) indicating that the absolutestructure has been determined correctly (Bijvœt pair analysis usingStudent's t distribution with 75% Bijvœt pairs coverage: 4049 pairsused). The method has also calculated that the probability that thestructure is inverted is equal to zero.

Thus these results indicate that the absolute configuration of Example3—compound of (Formula IB) is S (probability of 100%).

Example 5—RORγ GAL4 Reporter Gene Assay

Examples 2-3 of the present compound of Formula IA and Compound ofFormula IB application and example No. 37 from WO2015/082533 were testedfor their ability to inhibit RORγ activity in a RORγ GAL4 reporter geneassay.

The assay procedure is described below and results are presented inTable 1.

A GAL4 one-hybrid reporter system employing luciferase readout wasestablished to determine inhibition of RORγ in 293FT cells. The RORγligand-binding domain (LBD) was fused to the yeast GAL4 DNA bindingdomain (DBD) and placed under the control of the human cytomegalovirus(CMV) immediate early promoter, using expression vector pFN26A (Promega)and standard recombinant DNA cloning methods. To serve as a control inthe assay, a similar vector was generated in which the GAL4-DBD wasfused to Herpes simplex virus protein 16 (VP16), a constitutivetranscriptional activator.

To monitor the inhibitory effect of compounds on RORγ, a transcriptionalreporter construct was used. The pGL4.35 vector (Promega) contains ninecopies of the GAL4 Upstream Activator Sequence (UAS). This sequencedrives the transcription of the luciferase reporter gene luc2P inresponse to binding of a fusion protein containing the GAL4 DNA bindingdomain, as for example expressed by the GAL4-RORγ-LBD and GAL4-VP16expression vectors described above. To allow a GAL4 fusion protein todrive the expression of the luciferase reporter, the pGL4.35 expressionvector and the appropriate GAL4 fusion protein expression vector werebulk transfected in the 293FT cells using standard transfectiontechniques.

The day after transfection, cells were plated into 96 well plates, testcompound was added and the plates were incubated overnight.Subsequently, the firefly luciferase activity was quantified usingluciferase detection reagent and luminescence readout.

Detailed Assay Description

293FT cells (Invitrogen) were transfected with a GAL4 fusion proteinexpression vector (as described above) and the transcriptional reporterconstruct (pGL4.35, Promega). 60 μL of TransIT-293 transfection reagent(Mirus Bio) was added drop wise to 1500 μl Opti-MEM I Reduced SerumMedium (Invitrogen) and incubated at room temperature (RT) for 5 to 20minutes. 1500 μL of this reagent mixture was added to 5 μg of GAL4fusion protein expression vector and 5 μg of the transcriptionalreporter construct, and incubated at RT for 20 minutes.

To harvest 293FT cells from a T75 flask, first the culture medium wastaken off the cells. Subsequently, the cells were washed with PhosphateBuffered Saline (PBS) (Lonza), after which the PBS was removed. Todissociate the cells, 1 ml of TrypLE Express (Invitrogen) was added tothe flask, followed by incubation at RT until the cells visually startedto detach. Cells were collected in 5 mL of assay medium (DMEM culturemedium (Lonza), 10% dialyzed FBS (Invitrogen) and Pen/Strep (Lonza)) toachieve a single cell suspension. 10×10⁶ cells were spun down andre-suspended in 10 mL of assay medium. Subsequently, the cell suspensionwas added to the transfection mix tube, and then transferred as a wholeto a T75 flask (Greiner), followed by overnight (16-24 hours) incubationat 37° C. and 5% CO₂.

For compound screening, the cells were harvested (as described above)and counted. 13×10⁶ cells were spun down, the supernatant was aspiratedand the cells were re-suspended in 17.3 mL of assay medium to obtain acell suspension of 0.75×10⁶ cells/mL. 80 μL of cell suspension (60,000cells) was plated per well into a white, flat bottom, tissue culturetreated, 96 well screening plates (Greiner).

Test compounds were diluted, starting from a 10 mM dimethylsulfoxide(DMSO) stock solution, to serial dilutions in DMSO at 500× the finaltest concentration. Subsequently, these solutions were diluted to 5× thefinal test concentration in two 10-fold-dilution steps in assay medium.The final DMSO concentration of the 5× test compound solution was 1%. 20μL of the 5× test compound solution was added to each test well of the96 well plate previously plated with 80 μl cell suspension, resulting inthe final test concentration with 0.2% DMSO.

The plates were incubated overnight (16-24 hours) at 37° C. and 5% CO₂.

For the luciferase readout, the luciferase reagent (Britelite Plus,Perkin Elmer) was brought to RT. To each test well of the screeningplates, 100 μL of 2.5-fold diluted Britelite Plus reagent was added,followed by incubation at RT for 10 minutes. The luciferase luminescencesignal was measured using a Wallac Victor Microplate Reader (PerkinElmer).

The half maximum inhibitory concentration (10₅₀) values for the testcompounds were calculated from the luciferase signal using GraphPadPrism software (GraphPad Software).

Example 6—Peripheral Blood Mononuclear Cell (PBMC) IL-17 Assay

Examples 2-3 of the present application and example No. 37 fromWO2015/082533 were tested for their ability to inhibit the IL-17Aproduction in anti-CD3/anti-CD28 stimulated peripheral blood mononuclearcells (PBMCs) isolated from human blood. The assay procedure isdescribed below and results are presented in Table 1.

This assay is designed to measure the levels of IL-17A secreted fromanti-CD3/anti-CD28 stimulated PBMCs with the aim of measuring theinhibition of RORγ mediated IL-17A production.

Detailed Assay Description

The assay medium consists of 90% RPMI 1640 (Lonza), 10% heat-inactivatedfetal bovin serum (FBS, Lonza) and 100 U/mL penicillin/streptomycinsolution.

Anti-CD3 antibody (BD Pharmingen) was diluted to 10 μg/ml in PBS(Lonza). 30 μL of 10 μg/ml anti-CD3 solution was added to the inner 60wells of a 96-well cell culture treated U-bottom plate (Greiner). Plateswere incubated overnight (16-24 hours) at 37° C. and 5% CO₂.

Peripheral blood mononuclear cells were separated from buffy coats(Sanquin) using Ficoll-Paque PREMIUM separation medium (GE HealthcareLife Sciences) according to manufacturer's protocol and re-suspended inassay medium at 37° C.

Test compounds were diluted, starting from a 10 mM dimethylsulfoxide(DMSO) stock solution, to serial dilutions in DMSO at 200× the finaltest concentration. Subsequently, these solutions were diluted in twodilution steps in assay medium to 5× the final test concentration. TheDMSO concentration of the 5× test compound solution was 2.5%.

Anti-CD28 antibody (BD Pharmingen) was diluted to 10 μg/mL in assaymedium. The PBMCs were diluted to a concentration of 2.2×10⁶ cells/mL inassay medium at 37° C.

For compound screening, the anti-CD3 coated plates were washed two timeswith PBS; the wells were subsequently aspirated using vacuum. To eachscreening well 90 μL of the PBMC suspension, 30 μL of the anti-CD28solution and 30 μL of the 5× test compound solution was added, resultingin the final test concentration with 0.5% DMSO. All outer wells werefilled with PBS to prevent evaporation. Plates were incubated for 5 daysat 37° C. and 5% CO₂.

After incubation, the plates were spun down at 1500 rpm for 4 minutesand the supernatant was collected. Subsequently, the IL-17A levels inthe supernatants was determined using an IL-17A AlphaLISA kit (PerkinElmer) according to the manufacturer's protocol.

The half maximum inhibitory concentration (IC₅₀) values for the testcompounds were calculated from the IL-17A signal using GraphPad Prismsoftware (GraphPad Software).

TABLE 1 RORy GAL4 reporter gene PBMC IL-17 assay pIC₅₀ assay pIC₅₀Number Number Example Aver- Standard of experi- Aver- Standard of humanNo age deviation ments age deviation donors 37 7.9 0.2 5 7.9 0.2 11 27.4 0.2 5 7.2 0.2 11 3 7.9 0.2 5 7.6 0.3 11

Example 7—hERG Channel Protocol

Examples 2-3 of the present application and example No. 37 ofWO2015/082533 were tested in vitro against the hERG (humanEther-à-go-go-Related Gene) potassium channel. The assay procedure isdescribed below and results are presented in Table 2.

Detailed Assay Description

Frozen CHO (Chinese hamster ovary) cells stably expressing hERG channelswere thawed and seeded on glass coverslips in petri dishes. Cells werecultured in HAM's F-12 media supplemented with 10% fetal bovine serum,100 IU/mL penicillin, 100 μg/mL streptomycin and 500 μg/mL G418(Invitrogen, Carlsbad, Calif.) in an atmosphere of 95% air/5% CO₂ at 37°C. CHO cells were ready for patch-clamping after culture for 1-5 days.hERG currents were recorded at room temperature using the whole-cellpatch-clamp technique with an Axopatch 200B amplifier (MolecularDevices, Sunnyvale Calif.). Electrodes (1-3 MΩ resistance) werefashioned from TW150F glass capillary tubes (World PrecisionInstruments, Sarasota, Fla.) and filled with a solution containing (inmM): potassium aspartate 120; KCl 20; Na₂ATP 4; HEPES 5; MgCl₂ 1; pH 7.2adjusted with KOH. The external recording solution contained (in mM):NaCl 130; KCl 4; sodium acetate 2.8; MgCl₂ 1; HEPES, 10; glucose 10;CaCl₂ 1 at pH 7.4 adjusted with NaOH. hERG currents were elicited by 2 sdepolarizing pulses to +20 mV followed by repolarization to −40 mV for1.6 s from a −80 mV holding potential at a frequency of 0.1 Hz. Currentswere analyzed using the pCLAMP suite of software (Molecular Devices).IC₅₀ values of drugs were obtained using peak tail currents during the−40 mV step by nonlinear least-squares fit of the data (GraphPadSoftware, Inc. San Diego, Calif.).

Example 8—CYP3A4 Inhibition Protocol

Examples 2-3 of the present application and example No. 37 fromWO2015/082533 were tested for CYP3A4 inhibition using two differentprobes: midazolam and testosterone. The assay procedure is describedbelow and results are presented in Table 2.

Detailed Assay Description

Test compound dissolved in DMSO at selected concentrations was added toa phosphate buffer (50 mM, pH 7.4) containing human liver microsomes(0.1 mg/mL), MgCl (6 mM) and EDTA (0.5 mM) and CYP3A probe substrate,either midazolam (3 μM). Test compound was evaluated at theconcentrations 1, 3, 10 and 30 μM and the final DMSO concentration inthe incubation was 0.5%. After addition of 1 M NADPH the mixture wasincubated at 37° C. for 10 min (midazolam) or 30 min (testosterone). Thereaction was terminated by addition of cold CH3CN containing internalstandard, centrifuged and formation of the CYP3A specific metabolite(either 1′-hydroxymidazolam or 6-β-hydroxytestosterone) was quantifiedby UPLC-MS/MS. The relative CYP3A activity at each test concentrationwas calculated and IC₅₀ values determined using XLfit.

TABLE 2 CYP3A4 inhibition Assay IC₅₀, μM Midazolam Testosterone hERGinhibition Assay Example N^(o) probe probe IC₅₀, μM 37 10 2.8 4.3 2 2413 14.2 3 >30 16 11.2

The present application provides novel RORγ modulator compounds,Examples 2 and 3, which inhibit RORγ activity and for which both hERGinhibition and CYP3A4 inhibition were decreased when compared to priorart compound (example 37 from WO2015/082533). It therefore appears thatcompounds of (Formula IA) and of (Formula IB) limit the risks of cardiacsafety issues and potential adverse toxic effects related to drug-druginteractions respectively while maintaining the RORγ modulationactivity.

Example 9, 10, 11, 12 and 13: Synthesis of the Prodrugs Example9—Compound of (Formula VI):2-[4-(cyclopropylmethylsulfinyl)phenyl]-N-[4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide

Step 1

In a 100 mL three-neck round bottom flask placed under argon, hydrogenperoxide (2.64 mL, 25.88 mmol, 30% in water) was added dropwise to asolution of ethyl 2-[4-(cyclopropylmethylsulfanyl)phenyl]acetate (3 g,11.98 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-01 (12.53 mL, 113.84mmol). The reaction mixture was stirred for 30 minutes at RT, then a 10%aqueous solution of sodium thiosulfate (50 mL) was added, followed bybrine (10 mL). The aqueous layer was extracted twice with EtOAc. Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue was takeninto ACN (15 mL), concentrated under reduced pressure and dried underhigh vacuum to obtain 3.16 g of ethyl2-[4-(cyclopropylmethylsulfinyl)phenyl]acetate as a white solid.

MS(ES⁺) m/z 267.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ ppm 7.62 (d, J=8.28 Hz, 2H), 7.46 (d, J=8.28Hz, 2H), 4.09 (q, J=7.03 Hz, 2H), 3.76 (s, 2H), 2.72-2.87 (m, 2H), 1.18(t, J=7.15 Hz, 3H), 0.82-0.96 (m, 1H), 0.45-0.61 (m, 2H), 0.19-0.36 (m,2H).

Step 2

In a 100 mL round bottom flask, a 1M aqueous solution of sodiumhydroxide (5.41 mL, 5.41 mmol) was added to a solution of ethyl2-[4-(cyclopropylmethylsulfinyl)phenyl]acetate (400 mg, 1.50 mmol) inEtOH (25 mL). The reaction mixture was stirred overnight at RT and thenconcentrated under vacuum. The residue was taken into water, thenacidified with an aqueous solution of HCl 1N until reaching pH 1. Theaqueous layer was extracted three times with EtOAc. The combined organiclayers were washed once with brine, dried over Na₂SO₄, filtered andconcentrated under vacuum to obtain 306 mg of2-[4-(cyclopropylmethylsulfinyl)phenyl]acetic acid as a white solid.

MS(ES+) m/z 239.1 [M+H]+.

¹H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (d, J=8.28 Hz, 2H), 7.46 (d, J=8.28Hz, 2H), 3.66 (s, 2H), 2.71-2.89 (m, 2H), 0.85-0.96 (m, 1H), 0.46-0.64(m, 2H), 0.20-0.36 (m, 2H).

Step 3

2-(4-aminophenyl)-1,1,1,3,3-pentafluoro-propan-2-ol (151.8 mg, 0.63mmol), N-ethyl-N-isopropyl-propan-2-amine (0.33 mL, 1.89 mmol) and2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% inDCM, 0.48 mL, 0.82 mmol, dropwise) were added to a solution of2-[4-(cyclopropylmethylsulfinyl)phenyl]acetic acid (150 mg, 0.63 mmol)in DCM (25 mL), which had been prealably placed under argon in an icebath. After stirring for 30 minutes, the ice bath was removed and thereaction mixture was stirred overnight at RT. Then, DCM and water wereadded, and the aqueous layer was extracted twice with DCM. The combinedorganic layers were washed with a saturated aqueous solution of NaHCO₃,with a 0.5N aqueous HCl solution, with water, and finally with brine.The organic layer was dried with Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by column chromatography on silica gel,using from 98% to 95% DCM in MeOH as the eluent to give 206 mg of2-[4-(cyclopropylmethylsulfinyl)phenyl]-N-[4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamideas an off-white foam.

MS(ES⁺) m/z 462.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ ppm 10.35 (s, 1H), 7.45-7.79 (m, 9H),6.38-6.88 (m, 1H), 3.75 (s, 2H), 2.67-2.90 (m, 2H), 0.75-0.96 (m, 1H),0.45-0.62 (m, 2H), 0.14-0.37 (m, 2H).

Examples 10, 11, 12 and 13

The stereoisomers VIA and VID were separated from VI by chiralchromatography using a column Chiralpak AD 20 μm, 350×76.5 mm and amobile phase, Heptane:EtOH 50:50, 400 mL/min with UV detection at 254nm.

Starting from 160 mg of racemate in 100 mL of Heptane:EtOH 50:50, oneinjection of the solution was done to yield, after concentration, 34 mgof Example 10 (first enantiomer to be eluted), 35 mg of Example 13 (lastenantiomer to be eluted), and 70 mg of a mixture of Examples 11 and 12.

The stereoisomers VIB and VIC were separated from the correspondingmixture by chiral chromatography using a column Cellulose-4 5 μm,250×4.6 mm and a mobile phase, Heptane:EtOH 70:30, 45 mL/min with UVdetection at 254 nm.

Starting from 70 mg of the mixture in 8 mL of EtOH, four injections ofthe solution was done to yield, after concentration, 29 mg of VIB (firstenantiomer to be eluted), and 30 mg of VIC.

Example 10—Compound of (Formula VIA):(−)-2-[4-[(S)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1R)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide

Absolute configuration was assigned arbitrarily.

MS(ES⁺) m/z 462.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ ppm 10.35 (s, 1H), 7.66 (m, 3H), 7.63 (d,J=8.4 Hz, 2H), 7.56 (d, J=9.0 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.64 (t,J=53.2 Hz, 1H), 3.75 (s, 2H), 2.82 (dd, J=6.9 et 13.3 Hz, 1H), 2.74 (dd,J=7.7 et 13.3 Hz, 1H), 0.89 (m, 1H), 0.49 à 0.58 (m, 2H), 0.23 à 0.33(m, 2H).

Optical rotation: [α]_(D) ²⁰=−63.6° (c=3.8 mg/mL, DMSO).

Example 11—Compound of (Formula VIB):(−)-2-[4-[(S)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1S)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide

Absolute configuration was assigned arbitrarily.

MS(ES⁺) m/z 462.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 7.66 (m, 3H), 7.63 (d, J=8.4Hz, 2H), 7.56 (d, J=9.0 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.64 (t, J=53.2Hz, 1H), 3.75 (s, 2H), 2.82 (dd, J=6.9 et 13.3 Hz, 1H), 2.74 (dd, J=7.7et 13.3 Hz, 1H), 0.89 (m, 1H), 0.49 à 0.58 (m, 2H), 0.23 à 0.33 (m, 2H).

Optical rotation: [α]_(D) ²⁰=−83.1° (c=4.2 mg/mL, DMSO).

Example 12—Compound of (Formula VIC):(+)-2-[4-[(R)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1R)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide

Absolute configuration was assigned arbitrarily.

MS(ES⁺) m/z 462.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 7.66 (m, 3H), 7.63 (d, J=8.4Hz, 2H), 7.56 (d, J=9.0 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.64 (t, J=53.4Hz, 1H), 3.75 (s, 2H), 2.82 (dd, J=6.9 et 13.3 Hz, 1H), 2.74 (dd, J=7.7et 13.3 Hz, 1H), 0.89 (m, 1H), 0.49 à 0.58 (m, 2H), 0.23 à 0.33 (m, 2H).

Optical rotation: [α]_(D) ²⁰=+85.6° (c=5.8 mg/mL, DMSO).

Example 13—Compound of (Formula VID):(+)-2-[4-[(R)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1S)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide

Absolute configuration was assigned arbitrarily.

MS(ES⁺) m/z 462.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 7.66 (m, 3H), 7.63 (d, J=8.4Hz, 2H), 7.56 (d, J=9.0 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.64 (t, J=53.4Hz, 1H), 3.75 (s, 2H), 2.82 (dd, J=6.9 et 13.3 Hz, 1H), 2.74 (dd, J=7.7et 13.3 Hz, 1H), 0.89 (m, 1H), 0.49 à 0.58 (m, 2H), 0.23 à 0.33 (m, 2H).

Optical rotation: [α]_(D) ²⁰=+60.9° (c=3.8 mg/mL, DMSO).

Example 14—Aqueous Equilibrated Solubility

Sample Preparation

The studied compound was accurately weighted with a target concentrationof 2 mg/mL in an aqueous phosphate buffer (50 mM at pH=7.4). Thesolution was shaken overnight (rock'n roll shaker) at RT and protectedfrom light (about 24 hrs). The solution was filtered in plate filterdevice (microplate Millipore “Solvinert” with integrated PTFE filter;0.45 μm) and the filtrate was dosed by LC/UV method.

Reference (Standard) Preparation

The studied compound was accurately weighted with a target concentrationof 0.1 mg/mL in DMSO. The solution was sonicated at RT and protectedfrom light. The reference solution was dosed by a LC/UV method and pH ofthe solubilized fraction was measured.

TABLE 3 Example N^(o) Solubility pH 7.5* (μg/mL) 2 <1.0 3 <1.0 9 99.4 1094.8 11 92.5 12 94.4 13 93.0 *pH of the solubilized fraction.

The invention claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1, or a pharmaceutically acceptable salt thereof, wherein theabsolute configuration corresponds to a compound of Formula (IA),2-{4-[(cyclopropylmethyl)sulfonyl]phenyl}-N-{4-[(1R)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}acetamide:


3. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein the absolute configuration corresponds to acompound of Formula (IB),2-{4-[(cyclopropylmethyl)sulfonyl]phenyl}-N-{4-[(1S)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}acetamide:


4. A compound of formula (VI):

wherein the compound is selected from the group consisting of:2-[4-(cyclopropylmethylsulfinyl)phenyl]-N-[4-[1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide;(−)-2-[4-[(S)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1R)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide;(−)-2-[4-[(S)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1S)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide;(+)-2-[4-[(R)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1R)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide;and(+)-2-[4-[(R)-cyclopropylmethylsulfinyl]phenyl]-N-[4-[(1S)-1-(difluoromethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]acetamide,or a pharmaceutically acceptable salt thereof.
 5. A process of preparingthe compound of Formula (I) according to claim 1, comprising reacting anamine of formula (II)

with a compound of formula (III):

to generate the compound of Formula (I).
 6. A method for treatment ofrheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn'sdisease or multiple sclerosis comprising administering to a patient inneed thereof an effective amount of the compound according to claim 1,or a pharmaceutically acceptable salt thereof.
 7. A method for treatmentof rheumatoid arthritis, psoriasis, inflammatory bowel disease, Crohn'sdisease or multiple sclerosis comprising administering to a patient inneed thereof an effective amount of the compound according to claim 4,or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising the compound according to claim 1, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.
 9. The pharmaceuticalcomposition comprising the compound according to claim 4, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.
 10. A method for treatment ofosteoarthritis or asthma comprising administering to a patient in needthereof an effective amount of the compound according to claim 1, or apharmaceutically acceptable salt thereof.
 11. A method for treatment ofosteoarthritis or asthma comprising administering to a patient in needthereof an effective amount of the compound according to claim 4, or apharmaceutically acceptable salt thereof.
 12. A method for treatment ofmucosal leishmaniasis comprising administering to a patient in needthereof an effective amount of the compound according to claim 1, or apharmaceutically acceptable salt thereof.
 13. A method for treatment ofmucosal leishmaniasis comprising administering to a patient in needthereof an effective amount of the compound according to claim 4, or apharmaceutically acceptable salt thereof.
 14. A method for treatment ofKawaski disease or Hashimoto's thyroiditis comprising administering to apatient in need thereof an effective amount of the compound according toclaim 1, or a pharmaceutically acceptable salt thereof.
 15. A method fortreatment of Kawaski disease or Hashimoto's thyroiditis comprisingadministering to a patient in need thereof an effective amount of thecompound according to claim 4, or a pharmaceutically acceptable saltthereof.